Mice lacking surfactant protein (SP)-A (SP-A−/−) or SP-D (SP-D−/−) and wild-type mice were infected with group B streptococcus or Haemophilus influenzae by intratracheal instillation. Although decreased killing of group B streptococcus and H. influenzae was observed in SP-A−/− mice but not in SP-D−/− mice, deficiency of either SP-A or SP-D was associated with increased inflammation and inflammatory cell recruitment in the lung after infection. Deficient uptake of bacteria by alveolar macrophages was observed in both SP-A- and SP-D-deficient mice. Isolated alveolar macrophages from SP-A−/− mice generated significantly less, whereas those from SP-D−/− mice generated significantly greater superoxide and hydrogen peroxide compared with wild-type alveolar macrophages. In SP-D−/− mice, bacterial killing was associated with increased lung inflammation, increased oxidant production, and decreased macrophage phagocytosis. In contrast, in the absence of SP-A, bacterial killing was decreased and associated with increased lung inflammation, decreased oxidant production, and decreased macrophage phagocytosis. Increased oxidant production likely contributes to effective bacterial killing in the lungs of SP-D−/− mice. The collectins, SP-A and SP-D, play distinct roles during bacterial infection of the lung.
Surfactant protein (SP)-A and SP-D are members of the collectin subgroup of the mammalian C-type lectins that also includes mannose-binding lectin and conglutinin (1, 2). The collectins are thought to be involved in innate host defense against various bacterial and viral pathogens. The collectins form multimeric structures resembling C1q (the first component of the complement cascade), consisting of multimeric collagenous amino-terminal domains and globular carboxy-terminal, carbohydrate binding domains (2). The C-type lectins bind carbohydrate surfaces of many microorganisms mediating phagocytosis and killing by phagocytic cells (3).
SP-A and SP-D are produced primarily by alveolar type II cells and nonciliated bronchiolar cells in the lung. SP-A binds to specific cell surface receptors on alveolar macrophages (4) and type II epithelial cells (5). In vitro, SP-A stimulates macrophage chemotaxis (6) and enhances the binding of bacteria and viruses to alveolar macrophages (3). SP-D binds to alveolar macrophages (7), binds and increases macrophage association with Escherichia coli (8), Mycobacterium tuberculosis (9), and Pneumocystis carinii (10), but does not enhance phagocytosis of these organisms in vitro. SP-D binds and increases phagocytosis of strains of Pseudomonas aeruginosa without causing bacterial aggregation (11).
Alveolar macrophages are thought to play a critical role in host defense of the lung. Alveolar macrophages bind, phagocytose, and kill bacteria in association with cellular activation, release of intracellular proteases, and reactive oxygen species. Reactive oxygen species are released by activated alveolar macrophages, directly killing bacteria. In vitro, both SP-A and SP-D can stimulate alveolar macrophages to generate oxygen radicals, measured as chemiluminescence (12, 13). Similarly, in vivo, alveolar macrophages from SP-A-deficient mice have impaired generation of reactive oxygen species (14).
Despite considerable in vitro evidence that SP-A is involved in host defense, its role in vivo has only recently been demonstrated. SP-A-deficient mice produced by targeted gene inactivation are susceptible to bacterial and viral pneumonia (15, 16). In vitro evidence supports a role of SP-D in pulmonary host defense, possibly mediated by different mechanisms than SP-A. In this study, to assess the role of SP-A and SP-D in vivo, SP-A- or SP-D-deficient mice were infected intratracheally with group B streptococcus (GBS) or Haemophilus influenzae. Microbial killing, inflammation, uptake of bacteria, and oxygen-radical generation by alveolar macrophages were compared in SP-A−/− and SP-D−/− mice in vivo.
LeVine, AM, et al.
The Journal of Immunlogy 2000
